Protein degrading enzymes have a wide spectrum of specificities and functions. Consequently they take part in numerous reactions, physiological as well as pathological, in cells and tissues. The possibility to design specific inhibitors makes proteases interesting targets for new drugs for treatment of diseases.
The serine protease stratum corneum chymotryptic enzyme (SCCE; EC 3.4.21.-; Swiss Prot P49862, also named kalllkrein 7; (WO 95/00651; Hansson L, et al T. Cloning, expression and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase; J Biol Chem 1994, 269:19420-19426; Yousef et al. The KLK7 (PRSS6) gene, encoding for the stratum corneum chymotryptic enzyme is a new member of the human kalllkrein gene family—genomic characterization, mapping, tissue expression and hormonal regulation. Gene 2000, 254: 119-128) is preferentially expressed in cornifying epithelia. Several studies have suggested that SCCE may take part in desquamation of cornified cells by means of degrading intercellular parts of desmosomes (Egelrud T. Desquamation in the stratum corneum. Acta Derm Venereol 2000, 208: 44-45). In stratum corneum extracts SCCE is responsible for a major part of the total proteolytic activity and is considered as having a potential role in skin pathophysiology, e.g. by acting as activators of precursors of pro-inflammatory cytokines (Nylander-Lundquist E, Egelrud T. Formation of active IL-1 beta from pro-IL-1 beta catalyzed by stratum corneum chymotryptic enzyme in vitro. Acta Derm Venereol 1997: 77: 203-206), or of protease activated cell surface receptors (Macfarlane S R, et al. Proteinase-activated receptors. Pharmacol Rev 2001, 53: 245-282).
Furthermore, SCCE has been observed to be up-regulated in psoriasis lesions (Ekholm E, Egelrud T. Stratum corneum chymotryptic enzyme in psoriasis. Arch Dermatol Res 1999, 291: 195-200) and in chronic lesions of atopic dermatitis (Hansson L, et al. Epidermal overexpression of stratum corneum chymotryptic enzyme in mice; a model for chronic itchy dermatitis. J Invest Dermatol. 2002, 118: 444-449). Together these results show that there is a disturbance in the keratinocyte expression of SCCE in two diseases characterized by chronic inflammation, epidermal hyperproliferation, and scaling. Increased activity of SCCE present in the skin may indeed play a significant part in skin pathophysiology and the use of inhibitors of SCCE activity presents a new therapeutically principle for the treatment of skin diseases.
Transgenic mice over-expressing human scce mRNA under a viral promoter have been generated (WO 02/062135.) The only phenotypic changes observed were found in the skin, which showed several histological changes similar to those seen in chronic inflammatory skin diseases in humans. The transgenic mice expressed human SCCE in suprabasal epidermal keratinocytes, and were found to develop pathological skin changes including increased epidermal thickness, hyperkeratosis, and a dermal infiltrate consisting of macrophages and granulocytes. There was also disturbed keratinocyte differentiation, epidermal hyperproliferation, increased transepidermal water loss and an induction of MHC II expression by keratinocytes. Furthermore, with increasing age the majority of the transgenic animals showed signs of severe itch (Hansson L, et al. Epidermal overexpression of stratum corneum chymotryptic enzyme in mice; a model for chronic itchy dermatitis. J Invest Dermatol. 2002, 118: 444-449; Ny A, Egelrud T. Transgenic mice overexpressing a serine protease in the skin: Evidence of Interferon γ-independent MHC II expression by Epidermal Keratinocytes. Acta Derm Venereol. 2003, 83:323-327; Ny A, Egelrud T Epidermal hyperproliferation precedes decreased skin barrier function In mice overexpressing stratum corneum chymotryptic enzyme. Acta Derm Venereol. 2004, 84:18-22). These transgenic mice will provide a useful animal model for human skin disease for the development of new treatment strategies and in the evaluation of therapeutically useful inhibitors of SCCE.
SCCE has also been found to be highly over-expressed in ovarian cancer (Tanimoto H, et al. The stratum corneum chymotryptic enzyme that mediates shedding and desquamation of skin cells is highly overexpressed in ovarian tumour cells. Cancer 1999, 86:2074-82, Kyriakopoulou L G, et al. Prognostic value of quantitatively assessed KLK7 expression in ovarian cancer. Clin Biochem 2003, 36:135-43). Inhibition of SCCE activity is therefore considered as a new therapeutical principle for the treatment of ovarian cancer.